Tsuchiya Takahumi, Shimizu Hiroyuki, Shimomura Kenju, Mori Masatomo
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Am J Nephrol. 2003 Jul-Aug;23(4):222-8. doi: 10.1159/000072053. Epub 2003 Jul 1.
BACKGROUND/AIMS: Troglitazone is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria. There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function. We determined the effect of troglitazone on isolated rat mesangial cell proliferation.
We determined PPAR-gamma mRNA expression in isolated rat mesangial cells. Chronic effects of 10(-6) to 10(-4) mol/l troglitazone on mesangial cell proliferation and mitogen-activated protein (MAP) kinase activity were also determined. The effects of troglitazone on apoptosis were investigated in rat mesangial cells.
Rat PPAR-gamma mRNA was detected in isolated rat mesangial cells. Living cell number, assessed by colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly decreased with 10(-4) mol/l troglitazone. The addition of 10(-6) to 10(-4) mol/l troglitazone dose-dependently inhibited 5-bromo-2'-deoxyuridine (BrdU) uptake into isolated rat mesangial cells. The addition of 10(-4) and 10(-5) mol/l troglitazone significantly reduced MAP kinase activity. Troglitazone at the concentrations of 10(-6) to 10(-4) mol/l dose-dependently increased DNA fragmentation rates, indicating that troglitazone may cause apoptosis in rat mesangial cells. Bax and Bcl-xL proteins were not changed, although Bcl-2 proteins increased with troglitazone.
The present data demonstrated that troglitazone inhibits cell proliferation, and induces apoptosis in rat mesangial cells, raising a possibility that it directly affects renal function.
背景/目的：曲格列酮是噻唑烷二酮衍生物之一，是过氧化物酶体增殖物激活受体-γ（PPAR-γ）的高亲和力配体。体内研究表明曲格列酮可改善微量白蛋白尿。关于噻唑烷二酮衍生物对系膜细胞功能的直接作用的报道较少。我们测定了曲格列酮对分离的大鼠系膜细胞增殖的影响。
我们测定了分离的大鼠系膜细胞中PPAR-γ mRNA的表达。还测定了10⁻⁶至10⁻⁴mol/L曲格列酮对系膜细胞增殖和丝裂原活化蛋白（MAP）激酶活性的慢性影响。在大鼠系膜细胞中研究了曲格列酮对细胞凋亡的影响。
在分离的大鼠系膜细胞中检测到大鼠PPAR-γ mRNA。用比色法[3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑]（MTT）测定法评估，10⁻⁴mol/L曲格列酮使活细胞数量显著减少。添加10⁻⁶至10⁻⁴mol/L曲格列酮剂量依赖性地抑制5-溴-2'-脱氧尿苷（BrdU）摄取到分离的大鼠系膜细胞中。添加10⁻⁴和10⁻⁵mol/L曲格列酮显著降低MAP激酶活性。10⁻⁶至10⁻⁴mol/L浓度的曲格列酮剂量依赖性地增加DNA片段化率，表明曲格列酮可能导致大鼠系膜细胞凋亡。Bax和Bcl-xL蛋白未改变，尽管Bcl-2蛋白随曲格列酮增加。
目前的数据表明曲格列酮抑制大鼠系膜细胞的增殖并诱导其凋亡，这增加了它直接影响肾功能的可能性。
